Project Summary Alzheimer's disease (AD) is characterized by early and prominent changes in glucose metabolism and mitochondrial respiratory enzymes. In AD patients and asymptomatic apoE4 carriers regional brain glucose uptake is decreased. However, we do not understand why these changes occur, how they contribute to neurodegeneration, or whether they can be targeted therapeutically. To gain insight into how AD proteins change glucose metabolism, we developed innovative assays to measure glucose metabolism in cellular and mouse models of AD. With this approach, we can test our central hypothesis that, in AD, mutant (mut)-amyloid precursor protein (mutAPP) and ApoE4 inhibit distinct steps in glucose metabolism and the respiratory chain, resulting in energy failure and impaired pentose phosphate pathway (PPP) function. The overall objective of our proposed study is to determine how mutAPP and apoE4 alter glucose metabolism in neurons. We will accomplish this objective in two specific aims. (1) We will use live imaging and mass spectrometry to measure metabolic fluxes, and determine how mutAPP and ApoE4 disrupt glucose metabolism and bioenergetics in cultured neurons. (2) We will use metabolic imaging to determine how mutAPP and apoE4 converge to disrupt glucose metabolism with age in mice. Overall, these studies will i) provide important insights into how mutAPP and apoE4 converge to disrupt glucose metabolism and energy production, ii) develop clinically translatable metabolic imaging approaches for AD, and iii) form the basis for new therapeutic strategies to normalize neuronal metabolism in AD.